Conformationally constrained anesthetic steroids that modulate GABA(A) receptors

J Med Chem. 2000 Nov 2;43(22):4118-25. doi: 10.1021/jm000977e.


Various cyclic ether and other 3 alpha-hydroxyandrostane derivatives bearing a conformationally constrained hydrogen-bonding moiety were prepared. Their anesthetic potency and their binding affinity for GABA(A) receptors, measured by intravenous administration to mice and inhibition of [(35)S]TBPS binding to rat whole brain membranes, were compared with that of known anesthetic 3 alpha-hydroxypregnan-20-ones. Synthetic steroids with similar in vitro and in vivo activities to the endogenous 3 alpha-hydroxypregnan-20-ones all had an ether oxygen on the beta-face of the steroid D-ring. These results suggest that for optimal GABA(A) receptor modulation, the hydrogen bond-accepting substituent should be near perpendicular to the plane of the D-ring on the beta-face of the steroid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstanols / chemical synthesis*
  • Androstanols / chemistry
  • Androstanols / pharmacology
  • Anesthetics / chemical synthesis*
  • Anesthetics / chemistry
  • Anesthetics / pharmacology
  • Animals
  • Brain / metabolism
  • GABA Modulators / chemical synthesis*
  • GABA Modulators / chemistry
  • GABA Modulators / pharmacology
  • Hydrogen Bonding
  • In Vitro Techniques
  • Injections, Intravenous
  • Mice
  • Models, Molecular
  • Radioligand Assay
  • Rats
  • Receptors, GABA-A / drug effects*
  • Receptors, GABA-A / metabolism
  • Structure-Activity Relationship


  • Androstanols
  • Anesthetics
  • GABA Modulators
  • Receptors, GABA-A